Lower female survival from an opportunistic infection reveals progesterone-driven sex bias in trained immunity
Alexander P. Earhart,
Natalia G. Karasseva,
Kathryn M. Storey,
Benjamin Olthoff,
Md Bodruzzaman Sarker,
Kimberly G. Laffey,
Margaret J. Lange,
R. Scott Rector,
Laura C. Schulz,
Diana Gil,
Claudia M. Neuhauser,
Adam G. Schrum
Affiliations
Alexander P. Earhart
Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
Natalia G. Karasseva
Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
Kathryn M. Storey
Division of Biological Sciences, College of Arts & Science, University of Missouri, Columbia, MO 65212, USA
Benjamin Olthoff
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65212, USA
Md Bodruzzaman Sarker
Division of Animal Sciences, College of Agriculture, Food & Natural Resources, University of Missouri, Columbia, MO 65212, USA
Kimberly G. Laffey
Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
Margaret J. Lange
Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
R. Scott Rector
Department of Nutrition and Exercise Physiology, School of Medicine, University of Missouri, Columbia, MO 65212, USA; Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA; Research Service, Harry S. Truman Memorial VA Hospital, University of Missouri, Columbia, MO 65212, USA; NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
Laura C. Schulz
Department of Obstetrics, Gynecology, & Women’s Health, School of Medicine, University of Missouri, Columbia, MO 65212, USA
Diana Gil
Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA; NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA; Department of Surgery, School of Medicine, University of Missouri, Columbia, MO 65212, USA; Department of Chemical & Biomedical Engineering, College of Engineering, University of Missouri, Columbia, MO 65212, USA
Claudia M. Neuhauser
Division of Research, Department of Mathematics, University of Houston, Houston, TX 77204, USA
Adam G. Schrum
Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA; Division of Animal Sciences, College of Agriculture, Food & Natural Resources, University of Missouri, Columbia, MO 65212, USA; NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA; Department of Surgery, School of Medicine, University of Missouri, Columbia, MO 65212, USA; Department of Chemical & Biomedical Engineering, College of Engineering, University of Missouri, Columbia, MO 65212, USA; Corresponding author
Summary: Immune responses differ between females and males, although such sex-based variance is incompletely understood. Observing that bacteremia of the opportunistic pathogen Burkholderia gladioli caused many more deaths of female than male mice bearing genetic deficiencies in adaptive immunity, we determined that this was associated with sex bias in the innate immune memory response called trained immunity. Female attenuation of trained immunity varies with estrous cycle stage and correlates with serum progesterone, a hormone that decreases glycolytic capacity and recall cytokine secretion induced by antigen non-specific stimuli. Progesterone receptor antagonism rescues female trained immune responses and survival from controlled B. gladioli infection to magnitudes similar to those of males. These data demonstrate progesterone-dependent sex bias in trained immunity where attenuation of female responses is associated with survival outcomes from opportunistic infection.
